U.S. patent number 4,211,771 [Application Number 05/877,313] was granted by the patent office on 1980-07-08 for treatment of human viral diseases with 1-b-d-ribofuranosyl-1,2,4-triazole-3-carboxamide.
Invention is credited to Roland K. Robins, Joseph T. Witkowski.
United States Patent |
4,211,771 |
Witkowski , et al. |
July 8, 1980 |
**Please see images for:
( Certificate of Correction ) ** |
Treatment of human viral diseases with
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
Abstract
The compound 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide is
used to treat diseases in humans which are caused by viral
infections.
Inventors: |
Witkowski; Joseph T. (Morris
Township, Morris County, NJ), Robins; Roland K. (Provo,
UT) |
Family
ID: |
27495850 |
Appl.
No.: |
05/877,313 |
Filed: |
February 13, 1978 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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690912 |
May 28, 1976 |
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617432 |
Sep 29, 1975 |
3976545 |
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340332 |
Mar 12, 1973 |
3927216 |
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240252 |
Mar 31, 1972 |
3798209 |
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149017 |
Jun 1, 1971 |
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Current U.S.
Class: |
514/43; 536/28.7;
536/28.8 |
Current CPC
Class: |
C07H
13/04 (20130101); C07H 19/04 (20130101); C07H
19/056 (20130101) |
Current International
Class: |
C07H
19/00 (20060101); C07H 19/04 (20060101); C07H
13/00 (20060101); C07H 13/04 (20060101); C07H
19/056 (20060101); A61K 031/41 (); A61K 031/70 ();
C07H 019/12 () |
Field of
Search: |
;424/180 ;536/23 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Brown; Johnnie R.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of application Ser.
690,912 filed May 28, 1976, now abandoned which in turn is a
continuation-in-part of application Ser. No. 617,432 filed Sept.
29, 1975, now Pat. 3,976,545, which in turn is a division of
application Ser. No. 340,332 filed Mar. 12, 1973, now U.S. Pat. No.
3,927,216, which in turn is a continuation-in-part of application
Ser. No. 240,252 filed Mar. 31, 1972, now U.S. Pat. No. 3,798,209,
which in turn is a continuation-in-part of application Ser. No.
149,017 filed June 1, 1971, now abandoned. The disclosures of all
of these applications are herein incorporated by reference.
Claims
We claim:
1. A process of treating viral diseases in humans which comprises
administering to the human patients an antiviral agent which has as
its active component the compound
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide.
2. A process of treating viral diseases in humans which are caused
by poxviruses, herpes viruses, othomyxoviruses or paramyxoviruses
which comprises administering to the human patients an antiviral
agent which has as its active component the compound
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide.
3. The process of claim 2 wherein the viral disease is caused by a
member of the poxviruses.
4. The process of claim 2 wherein the viral disease is caused by a
member of the herpesviruses.
5. The process of claim 2 wherein the viral disease is caused by a
member of the othomyxoviruses.
6. The process of claim 2 wherein the viral disease is caused by a
member of theparamyxoviruses.
7. A process of treating viral diseases in humans comprising
administering to the human patients an effective amount of a
composition containing from about 0.01% to 50% by weight, based on
the total weight of the composition, of the compound
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide.
8. A process of treating viral diseases in humans which are caused
by poxviruses, herpes viruses, othomyxoviruses or paramyxoviruses
comprising administering to the human patient an effective amount
of a composition contianing from about 0.01% to 50% by weight,
based on the total weight of the composition of the compound
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide.
9. The process of claim 8 wherein the composition is administered
orally.
10. The process of claim 8 wherein the composition is administered
topically.
11. The process of claim 8 wherein the composition is administered
by injection.
12. The process of claim 8 wherein the composition is administered
via the respitory tract.
13. The process of claim 8 wherein the composition is administered
ophthalmically.
14. A process for treating viral hepatitis in humans which
comprieses administering to a patient an oral preparation
containing as its active ingredient the compound
1-B-D-ribofuranosyl 1,2,4-triazole-3-carboxamide in a total daily
dose of approximately 100 to 1000 milligrams of the compound.
15. The process of claim 5 for treating influenza in humans which
comprises administering to a patient a composition containing as
its active ingredient the compound
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide in a total daily
dose of approximately 100 to 1000 milligrams of the compound.
16. The process of claim 15 wherein the composition is administered
orally.
17. The process of claim 4 of treating herpes labialis, herpes
progenitalis, herpes zoster, and herpes gingivostomatitis in humans
which comprises administering to a patient a composition containing
as its active ingredient the compound
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide.
18. The process of claim 17 wherein the composition is administered
orally in a total daily dose of approximately 100 to 1000
milligrams of the compound.
19. The process of claim 17 wherein the composition is a topical
composition containing from about 0.5% to 5% of the compound.
20. A process for treating measles in humans which comprises
administering to a patient a composition containing as its active
ingredient the compound
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, in a total daily
dose of approximately 100 to 1000 milligrams of the compound.
Description
BACKGROUND OF THE INVENTION
Viral infections are known to be one of the most frequent causes of
human illness. Upwards of 300 different immunologic types of virus
have been associated with humans; however, not all of these are
identified with clinical recognizable diseases.
Many of these diseases, having once been acquired, render their
host free from further infections by the same agent by stimulating
a life-long immunologic response by the host to the viral agent. It
is by this very same mechanism that conquest of certain
virus-caused disease states has been achieved. By using prophylaxis
induced by either killed or attenuated viruses or infection with an
immunologically related virus which causes a very mild disease
state, vaccines have been developed, for smallpox, yellow fever,
polio, and some of the common childhood diseases, e.g. mumps,
rubella, and measles.
While prophylaxis from some viral diseases can be obtained by
immunity, immunologic protection from other viral diseases is not
possible because either prolonged immunity is not developed against
the virus, or the same clinically described disease is caused by a
large group of related viruses which are antigenically dissimilar
and do not produce cross immunity, e.g., common cold viruses.
Coupled with this lack of universal prophylaxis against all viral
diseases is the necessity to effect a cure in an already
established viral disease. In search for this cure of viral
diseases, several chemotherpeutic agents have been used. Included
in this group are amantadine (1-adamantanamine), methisazone
(1-methylisatin B-thiosemicarbazone), cytarabine (cytarabine
(cytosine arabinoside), 5-IDU (5-iodo-2'-deoxyuridine); however,
these agents are of either limited spectrum, e.g., amantadine is
only active against Type A influenze virus, cytarabine and 5-IDU
are not active against RNA viruses and they are quite toxic.
SUMMARY OF THE INVENTION
The compound 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide has
been shown to exhibit wide spectrum antiviral activity both in
vitro and in vivo. The present invention relates to the use of this
compound in treating diseases in humans which are caused by these
very same viral agents. Accordingly, to treat viral-caused diseases
in human patients, the antiviral properties of the compound
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide are utilized by
administering to the human patient either by injection, orally,
topically, ophthalmically, or via sprays or aerosols in the
respiratory tract, and effective chemotherapeutic amount of the
compound 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide.
Detailed Description of the Invention
In our sequentially co-pending applications Ser. Nos. 690,912 filed
May 28, 1976, 617,432 filed Sept. 29, 1975; 340,322 filed Mar. 12,
1973; 240,252 filed Mar. 31, 1972; and 149,017 filed June 1, 1971,
the disclosures of which are herein incorporated by reference, we
disclosed the compound
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide as an antiviral
agent. This compound was described as exhibiting wide spectrum
antiviral activity both in vitro and in vivo. Also included in our
specification as filed in applications Ser. Nos. 240,252 and
149,017, supra, was the association of some of these viruses with
human viral diseases.
Viruses are classified according to the type of nucleic acid they
contain. The RNA viruses contain ribonucleic acid and the DNA
viruses contain deoxyribonucleic acid. Further subdivision is made
into groups based upon physical and biochemical properties. The
classification of a few of the viruses however, remains vague and
is subject to change based upon further elucidation of their
properties.
Using the taxonomic classification of C. Andrewes and H. G.
Pereira, Viruses of Vertebrates, Third Edition, 1972, The Williams
and Wilkins Co., Baltimore, the RNA viruses are subdivided into the
groups Picornavirus, Reovirus, Unclassified Arbovirus,
Orthomyxovirus, Paramyxovirus, Arenavirus, Rhabdovirus,
Coronavirus, Togavirus, and Leukovirus. The Picornaviruses can then
be further divided into two subgroups, the Enteroviruses and the
Rhinoviruses. The Enterovirus subgroup includes poliovirus,
coxsackie virus, and echovirus. The Arbovirus classification is a
broad classification based upon association with arthprods which
serve as vectors in transmission of the virus to other species.
Many viruses originally classified as Arbovirus are now classified
as Togaviruses and Rhabodoviruses. The Orthomyxovirus group
includes influenza viruses A, B, and C. The Paramyxovirus group
includes mumps virus, measles virus (i.e., rubeola), respiratory
syncytial virus, and para-influenzas viruses 1, 2, 3 and 4. The
Rhabdovirus group includes rabies virus. Rubella is an unclassified
RNA virus.
The DNA viruses are subdivided into groups as Papovavirus,
Adenovirus, Herpesvirus, Poxvirus, Iridovirus, and Parvovirus. In
the Herpes group, viruses which infect man include herpes hominis
Types 1 and 2, Epstein-Barr virus, varicella, and cytomegalovirus.
Among the Poxviruses are variola, vaccinia, and mulluscum
contagiosum.
The classification of other viruses is unsettled, including
infectious and serum hepatitis and roseola infantum.
Representatives from all of the major taxonomic groups of viruses,
except the RNA Leukovirus and the DNA Paravovirus and Iridovirus
groups, have been associated with viral disease in humans.
Among the diseases associated with the Enteroviruses are:
nonspecific febrile illness, upper respiratory infections including
rhinitis, pharyngitis, conjunctivitis, and lymphonodular
pharyngitis; herpangina, acute laryngotracheo bronchitis,
pneumonitis and pleuritis, aseptic meningitis, epidemic
pleurodynia, pericarditis, myocarditis, congenital heart disease,
gastroenteritis, orchitis, lymphadenitis, and poliomyelitis. The
Rhinoviruses are associated with coryza and bronchitis in children
while the Coronaviruses are associated with coryza. The
Rhabdoviruses are associated with rabies and vesicular stomatitis
while the Arenoviruses include lymphocytic choriomeningitis and
zoonotic and epidemic hemorrhagic fevers. The Togoviruses and other
Arboviruses are associated with numerous fevers, encephalitis and
hemorrhagic fevers including eastern, western, and Venezuelan
equine encephalitis, St. Louis and California encephalitis, yellow
fever and dengue. The Reoviruses are the cause of many asymptomatic
infections and Colorado tick fever. Orthomyxoviruses are the causal
agents of influenza. The Paramyxoviruses are associated with
bronchitis, bronchiolitis, or bronchopneumonia in children, rhintis
and pharyngitis in adults and other acute febrile respiratory
infections, laryngotracheobronchitis, rubeola, and parotiditis.
Rubella is caused by an as yet unclassified RNA virus. The
Adenoviruses are associated with acute respiratory infections,
pharyngo conjunctival fever, febrile pharyngitis, infant viral
pneumonia, kerato conjunctivitis, and acute follicular
conjunctivitis. The Herpesviruses are associated with varicella,
herpes zoster, herpes genitalis, herpes labialis, acute
gingivostomatitis, herpetic keratoconjunctivitis, eczema
herpeticum, traumatic herpes, meningoencephalitis, infectious
mononucleosis, and cytomegalic inclusion disease. The Poxviruses
are associated with vaccinia, smallpox, mulluscum contagiosum, and
milers nodes. The Papovaviruses are associated with warts.
Uncharacterized are the infective agents of the diseases roseola
infantum, hepatitis A and B, Creutfeldt-Jakob disease, kuru
disease, subacute sclerosing panencephalitis and progressive
multifocal encephalopthy.
For the purposes of further illustrating the invention,
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide will be referred
to interchangeably as (a) the compound, (b) Ribavirin (nonpropriety
name adopted by the United States Adopted Names Council), or (c)
under its chemical name above.
The compound can be administered to the human patient by injection,
orally, topically, ophthalmically, or via the respiratory tract in
acrosols or drops. For systemic use the compound would be given in
an amount such that the total daily dose of the compound is from
about 50 milligrams to about 2500 milligrams. The normal preferred
range is from about 8.5 to 20 milligrams per kilogram of body
weight per day. Depending on the mode of administration, the
compound can be formulated with appropriated diluents to form
solutions, suspension, tablets, capsules, or syrups. For topical
and ophthalmic use, the compound can be formulated with the
appropriate diluents and carriers to form ointments, creams, foams,
and solutions having from about 0.01% to about 15% by weight,
preferably from about 1% to 10% by weight of the compound. In any
event, the actual amount should be sufficient to provide a
chemotherapeutically effective amount of the compound to the
patient, all of which will be readily within the ability of those
skilled in the art to determine given the disclosure herein.
The compounds can be administered directly into the upper
respiratory tract of humans by conventional nose drops or
insufflated into either the upper or both upper and lower
respiratory tracks via aerosol nasal sprays or chambers and tents
equipped with aerosol devices or other conventional inhalation
nebulizers or vaporizers.
By way of illustration only, a specific nasal drops formulation
would contain for each 1000 milliliters:
______________________________________
1-B-D-ribofuranosyl-1,2,-4-triazole-3-carboxamide 20.0 g Monobasic
Sodium Phosphate USP XIX 0.5421 g Dibasic Sodium Phosphate USP XIX
0.8655 g Sodium Chloride USP XIX 8.50 g Benzalkonium Chloride USP
XIX 0.10 g EDTA Na.sub.2 0.05 g Bidistilled Water g.s. to
Phenylethyl Alcohol 2 ml ______________________________________
For nasal aerosol application the compounds may be used in an
aerosol nasal spray, of the type described in U.S. Pat. No.
3,014,844, the disclosure of which is incorporated by reference
herein, containing the indicated quantity of the compound suspended
in a liquified propellant, such as a lower alkane (up to 5 carbon
atoms), a lower alkyl chloride, or a fluorinated or
fluorochlorinated lower alkane (available commercially under the
trademark "Freon"). Generally, the propellant is a gas at room
temperature and atmospheric pressure, has a boiling point below
about 65.degree. F. at atmospheric pressure, and of course, is
non-toxic. Particularly suitable as such propellants are
dichlorodi-fluoromethane ("Freon 12"), dichlorotetrafluoroethane
("Freon 14"), and trichloromonofluoromethane ("Freon 11"). When
used in the suspension, the compound should be finely divided, as
for example, smaller than 100 microns diameter, preferably not
greater than 25 microns and more preferably about 0.5 to 4 microns
diameter. It may also be advantageous to include a surface active
agent, preferably non-ionic, e.g., esters or partial esters of
fatty acids containing 6 to 22 carbon atoms such as caproic,
octoic, lauric, palmitic, stearic, linoleic, etc., to help avoid
agglomeration of the powder. Normally, only a relatively small
quantity of the surface active agent will be used, as for example,
from about 0.25 to about 1.0%, although larger quantities may be
used if desired. Similarly, the stated quantity of the antiviral
agent compound may be dissolved in the liquified propellant with
the aid of an appropriate solvent, as described in U.S. Pat. No.
2,868,691, the disclosure of which is also incorporated by
reference herein.
By way of illustration only, a specific nasal aerosol formulation
would contain:
______________________________________ %W/W
______________________________________
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 5.0 Sorbitan
Trioleate 1.0 "Freon 11" 25.0 "Freon 14" 25.0 "Freon 12" 44.0
Water, USP -- Alcohol, USP -- Dimethyl Ether -- Valve 50ul Susp.
Shot weight 65.7 mg. Assay, % W/W 4.8 Particle size range 3-10u
______________________________________
The compound can also be dissolved or suspended in a suitable
solvent and be administered as an aerosol using a propellant other
than a halogenated hydrocarbon, from an aerosol package equipped
with a self-metering valve, all of which is known to those skilled
in the art. For use in an aerosol chamber, a chamber equipped with
an atomizer such as a Collison atomizer is used. This allows
continuous treatment with small particle aerosols of the compound.
Generally in all aerosol applications, the use of particle sizes of
from about 1.0 to about 4 .mu.m in diameter allows the compound to
be deposited deep in the bronchial tree and in the alveolar
spaces.
For injection the compound would be in the form of a solution or
suspension. The compound would be dissolved or suspended in
physiological saline or other physiologically compatible solution
from about 10 to about 1500 milligrams of compound per milliliter
of solution.
By way of illustration only, two formulations of different
concentrations would contain for each 1000 milliliters:
______________________________________ 20% Injectable
______________________________________
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 200.00 g EDTA
Na.sub.2 0.05 g Sodium Benzoate 150.00 g Benzoic Acid 2.60 g Benzyl
Alcohol 10 ml Bidistilled Water q.s.f.
______________________________________ 10% Injectable
______________________________________
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 100.00 g EDTA
Na.sub.2 0.05 g Methyl Paraben 2.00 g Benzyl Alcohol 5 ml
Bidistilled Water ______________________________________
An injectionable solution also can be prepared which contains only
the compound and a suitable physiological buffer. When prepared in
a sterile manner and sealed into sterile vials, no preservatives
are needed. An illustration of such an injectable containing 10% by
weight of compound per volume, buffered at pH 5-5 would
contain:
______________________________________
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 150.00 g Sodium
Phosphate dibasic anhydrous 553.5 mg Potassium phosphate monobasic
13.077 gm Water USP q.s. ad. 1500 ml
______________________________________
For use in the eye the compound would be as an ophthalmic solution
or suspended in an ophthalmic ointment such as LacriLube (trademark
Allergan Pharmaceuticals).
By way of illustration only, a specific ophthalmic solution
formulation would contain for each 1000 milliliters:
______________________________________
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 20.00 g Monobasic
Sodium Phospate 0.5421 g Dibasic Sodium Phosphate 0.8655 g Sodium
Chloride 8.500 g Benzalkonium Chloride 0.100 g EDTA Na.sub.2 0.050
g Benzyl Alcohol 2 ml Bidistilled Water q.s.f.
______________________________________
The compound may be administered as an oral preparation, in either
capsule, tablet, oral suspension, or syrup form. The tablets or
capsules will contain from about 10 to 500 milligrams of the
compound per tablet or capsule. The required dose of the compound
will vary upon the condition of the patient, but will normally
range from approximately 50 to 1000 milligrams per day. The
capsules will be the usual gelatin capsules and will contain in
addition to the compound in the quantity indicated above, a small
quantity, for example less than 5% by weight, magnesium stearate or
other excipient, such as "Avicel" (micro-crystalline cellulose).
Tablets will contain the foregoing amount of the compound and a
binder, which may be a gelatin solution, a starch paste in water,
polyvinyl pyrilidone, polyvinyl alcohol in water, etc., with a
typical sugar coating.
The syrup will contain from about 50 mg to 200 mg per 5 milliliters
of syrup.
By way of illustration only, specific formulations for tablets,
capsules, and syrup would contain:
______________________________________ For 1,000 tablets:
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 200 g Starch USP
146 g Polyvinyl Pyrilidine USP 4 g Encompress 20 g Pre-gelatinized
Starch USP 20 g Magnesium Stearate USP 4 g Aerosil USP 2 g Talc USP
4 g and for each capsule:
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 100.0 Cellulose,
Microcrystalline 122.75 Magnesium Stearate 2.25 Total Weight 225.00
and for 1000 milliliters of syrup:
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 20.00 g Sorbitol
70% USP 400 cc Ethylparaben USP 0.9 g Propylparabene USP 0.3 g
EDTA.2Na USP 0.01 g Sodium Chloride USP 3.0 g Ponceau 4R (C.I.
16,255) 0.01 g (Martindale 26) Essence of Framboesa 2 cc (Firmench"
50,954 Propylene Glycol USP 50 cc Alcohol 96% USP 10 cc
Demineralized Water Q.S.P. 1000 cc
______________________________________
The compound is administered topically in an ointment, cream,
emulsion, foam, or topical solution, depending on the condition of
the viral skin infection to be treated. The compound is formulated
with the standard carriers and other ingredients commonly used for
such topical applications. Thus, ointments, by reason of a greasy
base, are recommended for chronic conditions, while creams,
emulsions, and topical solutions are recommended for acute and
subacute lesions. Unlike ointments, creams are generally water
soluble and exhibit vanishing properties. "Topical solution" refers
to a solution of active ingredients in a solvent material
intermediate in viscosity between creams and easily evaporable
solvents like alcohol, so that a balance of spreadability and
prolongation of action is achieved.
As exemplary of the many topical ointment, cream, and solution
formulations which may be generally applied are the following
combinations of materials:
Ointments
a. Petroleum with excipients.
b. Plastibase, a plasticized hydrocarbon gel available from Squibb,
Inc. and comprised of polyethylene and mineral oil.
Creams
a. Methyl paraben USP
Propyl paraben USP
Spermaceti USP
Sodium lauryl sulfate USP
Stearyl alcohol USP
Cotyl alcohol USP
Glycerin USP
Deionized water
b. Stearic acid
Propylene glycol
Sorbitan monostearate and oleate
Polyoxyethylene sorbitan monostearate
Citric acid
Methyl and propyl parabens
c. Water base
Potassium sorbate
Methyl and propyl parabens
Glycerol monostearate
Squalane
Polysorbate 80 USP
Spermaceti
Stearyl alcohol
Sorbital solution
d. Polyethylene glycol 400 USP
Propylene glycol
Carboxymethylene
Monoamylamine
Titanium dioxide
Butylated hydroxytoluene
Topical Solutions
a. Polyvinyl alcohol-water
b. Polyethylene glycol 400
Accordingly, then, the topical vehicles are commonly comprised of,
in addition to bodying agents, humectants, saponifying agents,
emulsifiers, solvents, penetrants, pH regulators, plasticizers,
emollients, preservatives, hardening agents, pigments, and
perfumes, all as is well known in the art.
For employment against vaginal infections, topical carriers
affording maximum distribution of the active agent are preferred.
Thus, the compound is formulated into creams, tablets, gels, foams,
and suppositories.
As exemplary of the many vaginal carriers with which the compound
can be formulated are the following:
Vaginal Creams
a. Glycerol monostearate
Corn oil
Glycerine
Benzoic acid
Glutamic acid
Water
b. Glycerine
Ethyl alcohol
Liquid petrolatum
Polyethylene glycol ether: fatty alcohol complex
Paraben preservatives
Vaginal Suppositories
a. Lactose
Polyethylene glycol 400
Polysorbate 80
Polyethylene glycol 4000
Glycerine
Lactic acid
b. Polyethylene glycol
Polyoxyethylene palmitate
Lactic acid
By way of illustration only, a specific vaginal tablet formulation
contain for each tablet:
______________________________________
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 250 mg Lactose USP
510 mg Starch USP 100 mg FD&C Yellow #5 15% aluminum lake 2.0
mg Pobidone M.S. 26-28 25 mg Alcohol spag-lg Quantity sufficient
Starch USP 70 mg Magnesium Sterate USP 50 mg Talcum USP 10.0 mg
Total 972 mg ______________________________________
Topical vehicles for vaginal applications are pH-adjusted to the
acid conditions under which normal bacteria flourish, so as not to
debilitate body defense mechanisms. The art-skilled, of course, are
well aware of this and other considerations involved in topical
deployment of chemotherapeutic agents.
The topical preparations contain effective virus inhibiting
proportions of the compound, e.g., from about 0.01% to about 15% by
weight of the total weight of the composition, preferably 2.5% to
5% by weight. Up to about 15% by weight may be employed in the
treatment of recalcitrant conditions. The quantity of the other
ingredients in such preparations, of course, are commensurate with
the quantities of such ingredients as normally used and
determination of appropriate formulations is readily within the
ability of the art-skilled given the disclosure herein.
By way of illustration only, specific topical formulations would
contain for each 100 g of such formulation:
______________________________________ a.
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 5.000 g Povidone
NF 13" 2.000 g Methylparaben USP 18 0.075 g Propylparaben USP 0.025
g Xalifin 15 20.000 g Purified Water 72.900 g b. Stearic Acid USP
XIX 18.0 g White Bees Wax USP XIX 2.0 g Polyethylenglycol -400
Monostearate 5.0 g Polyethylenglycol -1000 Monostearate 8.0 g BHT
Butylated Hydroxytoluene USP XIX 0.1 g Silicone Q - 2 - 2523 "Dow"
0.5 g 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide 5.0 g
Glycerin USP XIX 0.5 g Methyl Paraben USP XIX 0.09 g Propyl Paraben
USP XIX 0.03 g Phenylethyl Alcohol 0.1 ml Distilled Water 60.2 g
Total weight 90.0 g ______________________________________
It should be noted that the form in which the compound is
administered, of course, will depend upon the particular virus
infection being treated. For example, if the infection is caused by
influenza or parainfluenza and has manifested itself in the upper
respiratory tract, the mode of treatment could be the described
nasal drops or aerosol nasal spray since this would deliver most
effectively the agent to the site of the infection, or oral or
injection therapy may be indicated, depending on the severity of
the infection. A lower respiratory infection might also be treated
orally or by injection. If the injection is of a topical nature,
such as herpes labialis (cold sore, fever blister), herpes
genitalis (viral infection of the penis or of the vaginal area),
herpes zoster (shingles), varicella (chickenpox), Eczema
herpeticum, etc., the appropriate application would be by topical
application as described above, possible combined with oral
treatment or injection therapy, also as described above.
EXAMPLE 1
Varicella (chickenpox)
Eighteen patients between the ages of 7 months and 5 years were
treated with Ribavirin. The parameters use for the clinical
diagnosis of varicella were:
(a) Maculopapulosar eruption in different stages of
development.
(b) Primary lesions which appeared on the trunk.
(c) Palms which were not vesiculated.
The drug was given orally in capsules in individualized doses
ranging from 10 to 20 mg/kg of body weight per day for 5 days. Two
patients also had pneuonitis as a complication. Fever and general
discomfort was abated within 12 hours and involution of the lesions
was seen before 48 hours. After 72 hours all of the patients became
asymptomatic as opposed to a customary time period of 8 to 10
days.
EXAMPLE 2
Parotiditis (mumps)
Sixteen patients between the ages of 2 and 12 years were treated
with Ribavirin. The parameter for establishing the clinical
diagnosis of mumps was painful tumescence of the parotid glands. Of
the sixteen cases, twelve involved bilateral swelling. No
complications were noted. The drug was administered as per Example
1. Twelve hours following the initial treatment the painful
swelling of the glands improved. Disappearance of the condition was
noted within 24 hours in four cases and within 72 hours for the
remainder.
EXAMPLE 3
Pharyngotonsillitis and Bronchopneumonia
Five patients between the ages of 8 to 12 months, four with
pharyngotonsillitis and one with bronchopneumonia, all of suspected
viral etiology, were treated with Ribavirin as per Example 1. The
four pharyngotonsillitis patients showed rapid remission of the
clinical cessation of respiratory stress in 12 hours, remission of
hyperthermia and coughing in 36 hours, and abatement of symptoms in
72 hours.
EXAMPLE 4
Rubeola (Measles)
Using a double-blind placebo controlled protcol 20 patients ages 1
to 12 years diagnosed as having measles were divided into a placebo
group. Clinical parameters used to evaluate the treatment were:
fever, exanthem, cough, rhinorrhea, and malaise. Symptoms were
graded 0 through 4 wherein zero was absence of symptoms and 4 was
the highest severity observed. The drug control group received
Ribavirin at a dosage of 10 mg/kg of body weight/day/for 7 days. A
statistical significant difference in both duration of disease and
severity of symptoms was observed between the drug treated group
and the placebo group.
Mean symptom score of all patients in drum treated group and
placebo group and percent of patient having a score of one or
greater per day.
__________________________________________________________________________
Mean symptom score of all patients in drug treated group and
placebo group and percent of patient having a score at one or
greater per day. DAY 0 1 2 3 4 5 6 7
__________________________________________________________________________
Cough Drug mean score 3.3 2.3 1.8 1.1 .7 .1 .1 .1 Placebo mean
score 2.8 2.8 2.7 2.2 2.4 2.3 1.8 1.5 Drugs % with symptoms 100 100
90 80 70 10 10 10 Placebo % with symptoms 100 100 89 78 89 78 78 78
Fever Drug mean score 3.3 2.3 1.2 .3 .1 0 0 0 Placebo mean score
3.4 3.8 3.3 1.6 1.6 1.3 .9 .6 Drug % with symptoms 90 80 60 30 10 0
Placebo % with symptoms 100 100 100 100 78 67 44 33 Exantham Drug
mean score 1.7 3.0 1.4 .2 0 Placebo mean score 1.1 2.6 3.2 2.3 1.4
.7 .4 .2 Drug % with symptoms 70 100 70 20 0 Placebo % with
symptoms 67 89 100 100 78 33 11 11 Rhinorrhea Drug means score 2.9
1.6 .7 .3 .1 0 Placebo mean score 3.3 3.2 2.8 1.8 1.4 1.2 1.0 .8
Drug % with symptoms 90 70 50 30 10 0 Placebo % with symptoms 100
100 100 78 78 78 67 67 Malaise Drug mean score 3.6 2.4 1.4 .6 .1 0
Placebo mean score 3.8 3.7 3.4 3.1 2.7 2.2 1.1 .9 Drug % with
symptoms 100 90 70 50 10 0 Placebo % with symptoms 100 100 100 100
100 100 67 67 * Patient dropped out from study on second day of
observation
__________________________________________________________________________
EXAMPLE 5
Herpes Zoster
A. Topical Treatment
Sixteen patients with an initial illness consisting of various
neoplastic diseases and secondary herpes zoster were randomly
assigned into placebo and Ribavirin treated groups. Neither patient
nor treating physician were aware of these assignments during the
study. A topical ointment containing 5% Ribavirin was used. The
placebo received the same ointment but without the added drug.
Ointment was applied twice daily for 8 days. Criterion for
evaluation of effectiveness of therapy was duration of the zoster
illness as determined by length of pain and lesions.
The placebo group showed a 51/2 days average length of lesion and
an 81/2 days average length of pain. The Ribavirin group showed a
significant reduction of averge length of both lesion and pain to
51/2 days and 21/2 days, respectively.
B. Oral and Intravenous Treatment
Eighteen patients with herpes zoster were divided into three
groups, four were treated with Ribavirin 400 mg/day (100 g.i.d.)
given oraly for 8 days, ten were treated with Ribavirin 400 mg/day
(200 mg b.i.d.) for 8 days and four were analgesics and/or some
other medication, i.e., one patient received Darvon and aspirin,
one patient received Dipirone and Vitamin B.sub.12 and two patients
received Dipirone Criterian for evaluation of therapy against the
illness was evaluated by:
a. duration of the disease in days,
b. duration of the pain in days,
c. beginning of involution of the lesions present in days
d. Beginning of the decay at the scabs in days.
Both in oral and intravenous therapy showed statistically
significant effectiveness as compared to the group not treated with
Ribavirin.
__________________________________________________________________________
Analysis of Results Beginning of Beginning of Duration of Duration
of Pain Involution of Lesions Decay of Scabs Patient Number Disease
(Days) (Days) (Days) (Days)
__________________________________________________________________________
Control Group 1 6 8 8 12 2 8 8 7 10 3 4 6 3 6 4 10 10 10 12 Mean 7
8 7 10 Oral Ribavirin 5 4 6 2 4 6 4 6 2 6 7 5 6 3 5 8 3 2 3 8 Mean
4 5 2.6 5.75 Intravenous Ribavirin 9 3 5 3 5 10 6 2 2 5 11 2 -- 1 2
12 4 2 2 3 13 7 1 2 6 14 2 1 3 5 15 3 1 3 6 16 3 2 3 6 17 3 2 4 6
18 10 2 3 4 Mean 4.3 2.0 2.5 4.8 Summary of Mean and Statistical
evaluation of students to test Control 7 8 7 10 Oral Ribavirin 4 5
2.6 (p<0.01) 5.75 (p<0.05) Intravenous Ribavirin 4.3 2 (p<
0.001) 2.5 (p<0.05) 4.8 (p<0.001)
__________________________________________________________________________
EXAMPLE 6
Gastroenteritis
A patient, 6 months of age, with gastroenteritis did not respond to
the usual treatment. Therefore, the disease was suspected to be of
viral origin. The patient was treated with 100 mg of Ribavirin
every 24 hours. Symptoms diminished within 24 hours after the
beginning of Ribavirin treatment.
EXAMPLE 7
Mulluscum Contagiosum
Three patients aged 2 to 5 years with mulluscum contagiosum were
treated with Ribavirin as per Example 1 with good results.
EXAMPLE 8
Herpes Gingivostomatitis
Twenty patients diagnosed as having herpes gingivostomatitis were
treated using a double-blind placebo controlled protocol. Ten
patients were treated with Ribavirin 400 mg/day (100 mg g.i.d.) for
5 days orally and ten patients were treated with placebo g.i.d. The
patients were evaluated for severity and duration of pain, ulcers,
adenopathy and difficulty in speaking and swallowing. Comparison of
the duration in days of the mean of all patients in each group
showed a statistically significant difference in both duration of
pain and ulcers for the drug treated group.
______________________________________ Mean Duration in Days
Difficulty in Patient Speak- Swallow- Adeno- Group Pain Ulcers ing
ing pathy ______________________________________ Placebo 4.4 5.3
3.1 2.8 3.1 Ribavirin 2.7 (P 0.05).sup.a 3.4(p 0.01).sup.a 2.9 2.2
2.8 ______________________________________ .sup.a Students t
test
EXAMPLE 9
Meningo-encephalitis
A patient 18 months old with meningo-encephalitis complicated with
viral pneumonitis was treated with Ribavirin as per Example 1 for a
period of 7 days. Remission of the respiratory condition was
observed in 24 hours and recuperation of alertness, with the
disappearance of neurological signs was noted 48 hours later. A
second patient 3 years in age with less severe clinical signs
responded following 2 days of treatment. Treatment was continued
for 5 days.
EXAMPLE 10
Influenza B
Thirty male volunteers, all of whom lacked serum neutralizing
antibodies against the challenged Type B influenza virus, were
divided into drug and placebo groups using a double blind protocol.
The drug control group received Ribavirin in 200 mg doses three
times per day. The placebo group received placebo capsules three
times per day. After subjects were examined by a physician once a
day and graded for signs and symptoms on a scale of 0 to 3+, with 0
being not present, 1+ mild, 2+ moderate, and 3+ severe. Most of the
signs and symptoms occurred in both the Ribavirin-treated and
placebo-treated groups. However, the scores of some of the
constitutional symptoms, i.e., feverishness, sweating, malaise,
joint and muscle pains, and others, and of the respiratory symptoms
and nasal mucosal changes were generally lower in the drug-treated
subjects. Total sign and symptom scores by day for the two groups
indicate that scores for the Ribavirin-treated group were
consistently lower.
______________________________________ Distribution of
Ribavirin-treated and Placebo-treated Subjects in Four Classes of
Influenza Illness with Different Severity Illness Ribavirin-treated
Placebo-treated Score Subject Subject
______________________________________ 3+ 1 5 2+ 2 3 1+ 7 2 0 5 5
15 15 ______________________________________ Difference in Daily
Total Illness Scores Between Ribavirin-treated and Placebo-treated
Groups Day Post-challenge -1 0 1 2 3 4 5 6 7 8
______________________________________ Ribavirin-treated Group 0 0
5 194 191 160 82 13 0 1 Placebo-treated Group 1 1 28 319 312 279
115 29 3 0 ______________________________________
Virus titer isolation from nasal washings from both groups up to 8
days post-challenge was almost identical. No drug-related side
effects were observed.
EXAMPLE 11
Influenza A.sub.2
Ribavirin treatment was used in a double blind study during an
influenza outbreak in a closed boarding school population of
sixty-one girls aged 8 to 16 years. Six groups were selected from
the overall population, each group consisting of eight individuals
randomly selected as symptoms of influenza were first reported.
Patients in which the infection had already become well-established
were not used. Three groups were treated with Ribavirin 100 mg
three times per day and three groups with placebo capsules three
times per day. The virus was identified as influenza A.sub.2
/England from throat washings taken at the onset of the disease.
Subjective symptoms were obtained through direct questions to the
patients. The degree of severity of clinical signs of illness was
greater for placebo-treated as compared to Ribavirin-treated as
seen by the following summary.
______________________________________ Distribution of Clinical
Signs of Influenza in Patients Treated with Placebo or Ribavirin
Degree of Severity* (No. of Patients) Mild Moderate Severe Clinical
Pla- Pla- Pla- Sign cebo Drug cebo Drug cebo Drug
______________________________________ Fever 6 0 14 0 4 0 Malaise 6
2 14 2 4 0 Rhinitis (cough) 4 3 4 1 16 2 Pharyngitis 3 2 21 3 0 2
Gastroenteritis 0 0 0 0 0 0 Headache 3 1 19 2 2 0 Myalgia 15 0 0 3
0 0 Conjunctivitis 5 0 11 2 0 1
______________________________________ *Composite of determinations
made beginning 24 hours after initiation of therapy.
Summary of Influenza Illness Distribution Among Patients Treated
with Placebo or Ribavirin Degree of Illness Placebo-treated
Ribavirin-treated ______________________________________ Severe 16
2 Moderate 4 1 Mild 4 3 Absent 0 15
______________________________________
EXAMPLE 12
Influenza A
Using a double-blind placebo control protocol, thirty volunteers
were given an Influenza A, Victoria (H.sub.3 N.sub.2) challenge.
One patient developed an allergic complication to the challenge and
was dropped. The remaining patients (15 in placebo group and 14 in
drug group) were medicated with Ribavirin 1000 mg/day in divided
doses three times per day or identical leveling placebo
capsules.
The efficacy of the drug was evaluated by:
A. Symptoms: wherein the patients indication of feeling of eyes,
ears, nose, throat, lymph nodes, trachea, larnyx, chest,
gastro-intestinal system, skin and general systemic response was
graded. The severity was graded on a 0-3 basis with each site
having 2 to 5 parameters to be considered.
B. Signs: wherein the Physician assigned a severity score of 0-3
based on the physical signs observed at the above indicated sites.
Temperatures were also a part of the physical sign record.
C. Physicans opinion: wherein after observing the physical signs,
and recording the symptoms, the physician then assigned a severity
score of 0-3 to the following categories not ill, rhinitis,
pharyngitis, tracheobronchitis, pneumonia, systemic, or other.
D. Nasal virus isolates: wherein nasal washes were performed daily
from days 1-7 to determine the number of patients shedding virus
and concentration of that virus.
E. Serum Antibody: wherein blood was drawn at several in intervals
to determine the number of patients developing antibody and the
concentration of the antibody.
The challenge inoculum was chosen such that all volunteers were
expected to contract the induced viral disease and to recover from
the induced viral disease. The effectiveness of the drug was
measured by the reaction in the severity of the induced disease in
the drug treated group compared to the placebo treated group.
Comparison of disease severity of influenza infected drug and
placebo treated groups showed:
______________________________________ Mean* Ratio Total (Placebo/
Group Scores Drug) ______________________________________ Symptoms
Placebo 26.6 2.4:1 Drug 11.1 Signs Placebo 9.9 1.7:1 Drug 5.9
Physician's Placebo 8.1 2.3:1 opinion scores Drug 3.5
______________________________________ (*Group means were
determined after totaling daily scores for all subjects).
Comparison of duration of disease parameters in influenza infected
drug and placebo treated groups showed:
__________________________________________________________________________
Group No. Subjects Total days mean
__________________________________________________________________________
Symptom Scores .gtoreq.5 Placebo 8 23 2.9 drug 5 8 1.6 (p<0.05)a
Signs Scores .gtoreq.3 Placebo 6 18 3.0 drug 3 8 1.6.sup.b
Physician Opinion Scores .gtoreq.3 Placebo 7 15 Drug 2
(p<0.05).sup.c 3 (p 0.05) 1.5.sup.b Temperatures
.gtoreq.100.0.sup.d Placebo 5 12 2.4 Drug 0 (p<0.05).sup.c 0
0.sup.b
__________________________________________________________________________
.sup.a Mean evaluation by t test .sup.b Insufficient numbers for
mean evaluation t Test .sup.c Numbers evaluation by Fisher's exact
test or chi wquare analysis .sup.d only 8 am and 8 pm temperatures
compared.
Comparison of mean nasal virus titers (mean of positive samples) of
influenza infected drug and placebo treated groups showed:
______________________________________ VIRUS TITERS (Log .sub.10)
Days Group 1 2 3 4 5 6 7 ______________________________________
Placebo 1.5.sup.a 3.1 2.2 2.6 2.2 2.0 2.4 Drug 0.9 2.0 1.8 1.4 0.9
1.3 2.6 (p <0.05).sup.b ______________________________________
.sup.a Mean of positive samples .sup.b Statistical evaluation by t
test
Comparison of the number of isolates and the number of titers
10.sup.3 of influenza infected drug and placebo treated groups
showed:
______________________________________ No. Subjects No.
Samples.sup.a No. Samples Group Positive Positive Titers 10.sup.3
______________________________________ Placebo 11 38 12 Drug 9 30 4
(p <0.05).sup.b ______________________________________ .sup.a
105 total samples in placebo group and 98 in the ribavirin group
.sup.b Statistical evaluation by Chi square
Comparison of the subjects exhibiting a .gtoreq.4 fold rise in
antibody titer of influenza infected drug and placebo treated
groups showed:
______________________________________ Group No. Subjects Final
Titer ______________________________________ Placebo 8 22 Drug 8 21
______________________________________
The total days of moderate to severe symptoms and signs in the drug
treated group were significantly less than those of the placebo
group, and the total days with at least one temperature of
100.degree. F. or greater were significantly lower in the virus
treated group compared to the placebo group.
That consistently higher concentrations of virus were detected in
nasal washes from Placebo subjects than from Ribavirin treated
subjects. In addition more virus isolations and titers 10.sup.3
were observed from Placebo samples than Ribavirin treated
samples.
That both groups exhibited comparable rates and degrees of antibody
production.
EXAMPLE 13
Herpes Labialis
Seventeen patients between the ages of 1 and 7 years with Herpes
labialis were treated as per Example 1. Satisfactory remission of
symptoms were observed by the second or third day of treatment.
Recurrence of symptoms occurred in two patients.
EXAMPLE 14
Acute Viral Hepatitis
Eight patients between the ages of 2 and 14 years were treated as
per Example 1. Treatment considerably curtailed the development of
symptoms with normalization of the transaminases in 3 to 4 days and
remission of the clinical symptoms in 5 to 8 days.
In a second study, sixty-six patients with the clinical diagnosis
of acute viral hepatitis were divided into two groups and treated
using a double blind protocol with either a 0.25 g placebo capsule
or a 0.25 g capsule containing 0.10 g of Ribavirin every 6 hours.
The published results of this study, i.e., Action of
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Ribavirin) on
Acute Viral Hepatitis, Paulo Augusto Ayrosa Galvao, Ann. N.Y. Acad.
Sci., 284, 278 (1977) are herein expressly incorporated by
reference. The study can be summarized as follows:
The effect of Ribavirin was evaluated by the clinical picture and
by the changes in both direct and total serum bilirubin and in the
activity of serum glutamic pyruvic (SGPT) and glutamic oxalo-acetic
(SGOT) transaminases. There was a statistically significant
decrease in serum bilirubin, SGOT and SGPT from the 5th to the 10th
day of treatment for the Ribavirin-treated group. The decrease
noted for the placebo group was not statistically significant.
EXAMPLE 15
Herpes Progenitalis
Fifty patients having severe, recurrent herpes progenitalis of a
duration of at least one year and a minimum of 4 to 6 episodes
during the previous 12 months were evaluated using a double-blind
placebo protocol. The drug treated patients were given Ribavirin at
800 mg/day (200 mg g.i.d.) for 10 days. This course of treatment
was repeated a second and third time in certain instances. After
the first course of treatment 18 patients did not return for a
second treatment and of the 30 patients in this phase of the study,
15 patients dropped out from a third course of treatment. On
telephone follow-up most reported no recurrence and a few could not
be contacted. Patients were usually seen within 24 hours of onset
of lesions to confirm clinical diagnosis and for routine blood and
urine tests. Once treatment was initiated patients were seen every
other day. Patient's response was recorded noting features such as
pain, new vesicles, old vesicles, erythema and edema and ulcers.
Pain response to treatment was scored 0 to 4; new vesicles and old
vesicles response to treatment was scored 0 to 2, erythema and
edema and ulcers response to treatment was scored 0 to 3. Zero was
always no response and the higher number corresponded to best
response to ribavirin's therapy.
When the study was completed, individual codes were broken and the
patients assigned to drug or placebo groups. The weighted score for
each patient and for each course of treatment were evaluated
separately for each therapeutic trail. Where patient results could
be followed through one, two or three courses of treatment,
ribavirin consistently showed a highly statistically significant
(P=0.001) diminution of duration of disease and severity of signs
and symptoms as compared to the placebo group. Recurrences were
observed in both groups, but because some patients could not be
followed to the completion of the study, no definitive conclusions
are drawn with regard to ribavirin's efficacy in preventing
recurrences or in diminishing the frequency and severity of such
recurrences.
All of the scores of the patients in each group were added together
and the mean score determined. The following table shows these mean
patient scores and also the study t value and probability of this
value for day 3-10.
__________________________________________________________________________
Ribavirin Placebo Day Day 3 5 7 10 3 5 7 10
__________________________________________________________________________
First Treatment Ulcers Mean 1.6 1.9 2.5 2.6 1.7 2.0 2.0 2.0 t-value
4.5 (P<0.001) 1.2 (P<0.2) Erythema and Edema Mean 1.4 1.7 2.2
2.3 1.7 1.9 1.7 1.8 t-value 4.7 (P<0.001) .4 (P<0.8) Old
Vesicles Mean .9 1.2 1.6 1.8 .9 1.2 1.1 1.1 t-value 7.1
(P<0.001) 1.4 (P<0.2) New Vesicles Mean 1.1 1.2 1.6 1.8 1.6
1.7 1.7 1.7 t-value 5.0 (P<0.001) .8 (P<0.5) Degree of Pain
Mean 2.8 3.0 3.7 3.7 2.7 2.9 2.9 2.9 t-value 4.8 (P<0.02) 0.5
(P<0.8) Second Treatment Ulcers Mean 2.1 2.4 2.9 3.0 1.9 2.1 2.1
2.2 t-value 4.8 (P<0.001) .9 (P<0.5) Erythema and Edema Mean
1.4 1.6 2.1 2.4 1.2 1.4 1.4 1.4 t-value 3.8 (P<0.001) .6
(P<0.8) Old Vesicles Mean 1.1 1.3 1.9 1.9 1.1 1.3 1.3 1.3
t-value 4.1 (P<0.001) .8 (P<0.5) New Vesicles Mean 1.4 1.8
1.9 2.0 1.6 1.7 1.1 1.3 t-value 4.6 (P<0.001) .98 (P<0.5)
Degree of Pain Mean 2.8 3.3 3.7 4.0 3.0 3.4 3.5 3.6 t-value 4.9
(P<0.001) 2.1 (P<0.05) Third Treatment Ulcers Mean 1.7 2.2
2.7 2.8 1.7 2.0 1.9 1.7 t-value 4.0 (P<0.001) 0 Erthema and
Edema Mean 1.8 2.2 2.3 2.3 2.1 1.7 1.1 1.1 t-value 2.0 (P<0.05)
2.3 (P<0.05) Old Vesicles Mean 1.4 1.7 1.8 1.8 1.4 1.4 1.1 1.4
t-value 1.5 (P<0.1) .7 (P<0.5) New Vesicles Mean 1.3 1.7 2.0
1.8 1.9 1.7 1.7 1.7 t-value .28 (P<0.02) .4 (P<0.8) Degree of
Pain Mean 2.7 3.2 3.6 3.8 2.8 3.3 3.0 3.0 t-value 2.7 (P<0.02)
.37 (P<0.8)
__________________________________________________________________________
Evidence has implicated a measles-like virus with the demyelinating
diseases of multiple sclerosis and subacute sclerosing
panencephalitis. Progressive multifocal encephalopthy is associated
with a human papovaviruses.
In Sjogren Syndrome, systemic lupus erythematosus, and rheumatoid
arthritis physical damage is caused by auto-immune response
however, certain evidence, including the discovery of viral-like
inclusions, suggest that the virus might be the primary cause of
these diseases.
Rubella virus is teratogenic and if a mother is infected during the
first trimester of pregnancy, there is a high chance that birth
defects will result. Transient arthritis is also seen following
rubella or vaccination with certain rubella vaccines.
1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide has been given to
terminally ill patients, in a tolerance study. Does up to 26 2600
milligrams per square meter (mg/m.sup.2)tid (equal to 12,600
mg/day) three times per day have been tolerated. This high dose
produced an anemia which was reversible upon withdrawal of the
drug.
* * * * *